chr19-4090590-G-A

Position:

• chr19-4090590-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP7 BP5

This summary comes from the ClinGen Evidence Repository: The c.*8C>T variant in the MAP2K2 gene is located in the untranslated mRNA region downstream of the termination codon. The filtering allele frequency in gnomAD v4.1.0 is 0.01257%(172/1145270 alleles) in non-Finnish European population (PM2_Supporting/BS1/BA1 are not met). This variant is at a nucleotide that is not highly conserved and is not predicted to impact splicing (BP7). The c.*8C>T variant has been observed in at least 6 individuals who underwent testing for RASopathies (PS4 not met; GeneDx, LMM internal data; GTR ID's: 26957, 21766; SCV000063150.4, SCV000170190.9). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx internal data, SCV000170190.9). In summary, this variant meets criteria to be classified as likely benign for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BP5, BP7 (Specification Version 2.1, 09/17/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA137903/MONDO:0021060/048

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: MAP2K2 NM_030662.4 3_prime_UTR
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:4
• Conservation: PhyloP100: -0.0700

Genes affected

MAP2K2 (HGNC:6842): (mitogen-activated protein kinase kinase 2) The protein encoded by this gene is a dual specificity protein kinase that belongs to the MAP kinase kinase family. This kinase is known to play a critical role in mitogen growth factor signal transduction. It phosphorylates and thus activates MAPK1/ERK2 and MAPK2/ERK3. The activation of this kinase itself is dependent on the Ser/Thr phosphorylation by MAP kinase kinase kinases. Mutations in this gene cause cardiofaciocutaneous syndrome (CFC syndrome), a disease characterized by heart defects, cognitive disability, and distinctive facial features similar to those found in Noonan syndrome. The inhibition or degradation of this kinase is also found to be involved in the pathogenesis of Yersinia and anthrax. A pseudogene, which is located on chromosome 7, has been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP2K2	NM_030662.4	c.*8C>T		3_prime_UTR_variant	11/11	ENST00000262948.10
MAP2K2	XM_006722799.3	c.*8C>T		3_prime_UTR_variant	9/9
MAP2K2	XM_047439100.1	c.*8C>T		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP2K2	ENST00000262948.10	c.*8C>T		3_prime_UTR_variant	11/11	1	NM_030662.4	P1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000109 AC: 17 AN: 155612 Hom.: 0 AF XY: 0.000134 AC XY: 11 AN XY: 82292

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000404

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000884

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000235

Gnomad OTH exome AF: 0.000227

GnomAD4 exome AF: 0.000130 AC: 182 AN: 1395756 Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 93 AN XY: 688692

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000280

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.000196

Gnomad4 SAS exome AF: 0.0000253

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000145

Gnomad4 OTH exome AF: 0.000242

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152210 Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7 AN XY: 74356

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000200 Hom.: 0

Bravo AF: 0.000110

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:4

Revision: reviewed by expert panel

Submissions by phenotype

not specified Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 13, 2018	Variant summary: MAP2K2 c.*8C>T is located in the untranslated mRNA region downstream of the termination codon. The variant allele was found at a frequency of 0.00014 in 179598 control chromosomes. The observed variant frequency is approximately 55 fold of the estimated maximal expected allele frequency for a pathogenic variant in MAP2K2 causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is benign. c.*8C>T has been reported in the literature in individuals affected with autism. This report does not provide unequivocal conclusions about association of the variant with Noonan Syndrome and Related Conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinGen RASopathy Expert Panel has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign based on ACMG criteria BP5 and BP7 although the variant is not a synonymous variant type. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 10, 2009	- -

RASopathy Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen RASopathy Variant Curation Expert Panel

May 09, 2017

The c.*8C>T variant in MAP2K2 has been observed in at least 6 individuals who underwent testing for RASopathies (PS4 not met; GeneDx, LMM internal data; GTR ID's: 26957, 21766; SCV000063150.4, SCV000170190.9). This variant is a synonymous (silent) variant at a nucleotide that is not highly conserved and is not predicted to impact splicing (BP7). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx internal data, SCV000170190.9). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BP7, BP5. -

Noonan syndrome and Noonan-related syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 13, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	3.7
DANN	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs377675706; hg19: chr19-4090588;